EPIRUBICIN HYDROCHLORIDE 2 MG / ML SOLUTION FOR INJECTION OR INFUSION - summary of medicine characteristics

Epirubicin Hydrochloride 2 mg/ml solution for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 2 mg epirubicin hydrochloride.

Each 5/10/25/50/100 ml vial contains 10/20/50/100/200 mg epirubicin hydrochloride.

Excipient: Contains sodium 3.54 mg/ml (0.154 mmol).

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Solution for injection or infusion

A clear red solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Epirubicin is used in the treatment of a range of neoplastic conditions including;

■ Carcinoma of the breast

■ Gastric cancer

When administered intravesically, epirubicin has been shown to be beneficial in the treatment of

Papillary transitional cell carcinoma of the bladder

Carcinoma-in-situ of the bladder.

Prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection

4.2 Posology and method of administration

Epirubicin is for intravenous or intravesical use only.

The safety and efficacy of epirubicin in children has not been established

Intravenous administration

It is advisable to administer epirubicin via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation (see section 4.4). In case of extravasation, administration should be stopped immediately.

Conventional dose

When epirubicin is used as a single agent, the recommended dosage in adults is 60–90 mg/m2 body area. Epirubicin should be injected intravenously over 3–5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient's hae­matomedullary status.

If signs of toxicity, including severe neutropenia/ne­utropenic fever and thrombocytopenia occur (which could persist at day 21), dose modification or postponement of the subsequent dose may be required.

High dose

Epirubicin as a single agent for the high dose treatment of lung cancer should be administered according to the following regimens:

Small cell lung cancer (previously untreated): 120 mg/m2 day 1, every 3 weeks.

For high dose treatment, epirubicin may be given as an intravenous bolus over 3–5 minutes or as an infusion of up to 30 minutes duration.

Breast Cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin ranging from 100 mg/m2 (as a single dose on day 1) to 120 mg/m2 (in two divided doses on days 1 and 8) every 3–4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen (in accordance with local guidelines) are recommended.

Lower doses (60–75 mg/m2 for conventional treatment and 105–120 mg/m2 for high dose treatment) are recommended for patients whose bone marrow function has been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone marrow infiltration. The total dose per cycle may be divided over 2–3 successive days.

The following doses of epirubicin are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

aDoses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

Combination therapy

If epirubicin is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above. In establishing the maximal cumulative doses of Epirubicin (usually: 720 – 1000 mg/m2), any concomitant therapy with potentially cardiotoxic drugs should be taken into account.

Impaired liver function

The major route of elimination of epirubicin is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

*AST – aspartate aminotransfera se

Impaired renal function

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450^mol/l).

Intravesical administration

Epirubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be given intravesically for the treatment of invasive tumours that have penetrated the bladder wall, systemic therapy or surgery is more appropriate in these situations (see section 4.3). Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

If local toxicity is observed: A dose reduction to 30 mg/50 ml is advised.

Carcinoma-in-situ: Up to 80 mg/50 ml (depending on individual tolerability of the patient)

For prophylaxis: 4 weekly administrations of 50 mg/50 ml followed by 11 monthly instillations at the same dose.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

The solution should be retained intravesically for 1– 2 hour. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.

4.3 Contraindications

Epirubicin is contraindicated in:

Patients who have demonstrated hypersensitivity to the active substance or to any of the excipients, other anthracyclines or anthracenediones.

Lactation

Intravenous use:

Patients with persistent myelosuppression

severe hepatic impairment

severe myocardial insufficiency

recent myocardial infarction

severe arrhythmias

previous treatments with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones (see section 4.4)

patients with acute systemic infections

unstable angina pectoris

myocardiopathy

Intravesical use:

Urinary tract infections.

Invasive tumours penetrating the bladder.

Catheterisation problems.

Inflammation of the bladder.

Hematuria

4.4 Special warnings and precautions for use

General

Epirubicin hydrochloride should be administered only under the supervision of a qualified physician who is experienced in the use of cytotoxic therapy.

Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment before beginning treatment withepirubicin hydrochloride.

While treatment with high doses of epirubicin hydrochloride (e.g., > 90 mg/m2 every 3 to 4 weeks) causes adverse events generally similar to those seen at standard doses (< 90 mg/m2 every 3 to 4 weeks), the severity of the neutropenia and stomatitis/ mucosal inflammation may be increased. Treatment with high doses of epirubicin hydrochloride does require special attention for possible clinical complications due to profound myelosuppression.

Cardiac Function – Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or late (i.e., delayed) events.

Early (i.e., Acute) Events. Early cardiotoxicity of epirubicin hydrochloride consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for the discontinuation of epirubicin hydrochloride treatment.

Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin hydrochloride or within 2 to 3 months after treatment termination, but later events (several months to years after completion of treatment) have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution (see section 5.1).

Cardiac function should be assessed before patients undergo treatment with epirubicin hydrochloride and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of epirubicin hydrochloride at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.

Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m2 epirubicin hydrochloride should be exceeded only with extreme caution.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pe­ricardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab) (see section 4.5) with an increased risk in the elderly.

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzumab therapy alone or in combination with anthracyclines such as epirubicin hydrochloride. This may be moderate to severe and has been associated with death.

Trastuzumab and anthracyclines such as epirubicin should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of traztuzumab and anthracyclines.

Because the reported half-life of trastuzumab is approximately 28–38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as epirubicin after stopping trastuzumab may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin hydrochloride are used, the patient's cardiac function should be monitored carefully (see section 4.5).

If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin hydrochloride therapy, it should be treated with the standard medications for this purpose.

Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present. It is probable that the toxicity of epirubicin hydrochloride and other anthracyclines or anthracenediones is additive.

Haematologic Toxicity As with other cytotoxic agents, epirubicin hydrochloride may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin hydrochloride, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopoenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin hydrochloride haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopoenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocy­topenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.

Secondary Leukaemia – Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin hydrochloride. Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemia's can have a 1– to 3-year latency period. (See section 5.1).

Gastrointestinal – Epirubicin hydrochloride is emetigenic. mucosal inflammation /stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.

Liver Function – The major route of elimination of epirubicin hydrochloride is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin hydrochloride. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients (see sections 4.2 and 5.2). Patients with severe hepatic impairment should not receive epirubicin hydrochloride (see section 4.3).

Renal Function – Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dL (see section 4.2).

Effects at Site of Injection – Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/throm­bophlebitis at the injection site (see section 4.2).

Extravasation – Extravasation of epirubicin hydrochloride during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of epirubicin hydrochloride, the drug infusion should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (please refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool using hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.

Other – As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin hydrochloride

Tumour-Lysis Syndrome – Epirubicin hydrochloride may induce hyperuricemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumour-lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections- Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin hydrochloride,may result in serious or fatal infections. (see section 4.5). Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Reproductive system: Epirubicin hydrochloride can cause genotoxicity. Men and women treated with epirubicin hydrochloride should adopt appropriate contraceptives measures. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.

Intravesical route – Administration of epirubicin hydrochloride may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumours).

Intra-arterial route – Intra-arterial administration of epirubicin hydrochloride (transcatheter arterial embolisation for the localized or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of epirubicin hydrochloride) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.

Excipient (s) that the clinician should be aware of:

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Epirubicin hydrochlorideis mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/haematologic and gastrointestinal effects (see section 4.4). The use of epirubicin hydrochloride in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout treatment.

Epirubicin hydrochloride is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin hydrochloride metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity (see section 4.4 Special warnings and precautions for use).

Anthracyclines including epirubicin hydrochloride should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The half-life of trastuzumab is approximately 28–38 days and may persist in the circulation for up to 27 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.

Vaccination with a live vaccine should be avoided in patients receiving epirubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Cimetidine increased the AUC of epirubicin by 50% and should be discontinued during treatment with epirubicin hydrochloride.

When given prior to epirubicin hydrochloride, paclitaxel can cause increased plasma concentrations of unchanged epirubicin hydrochloride and its metabolites, the latter being, however, neither toxic nor active. Coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin hydrochloride when epirubicin hydrochloride was administered prior to the taxane.

This combination may be used if using staggered administration between the two agents. Infusion of epirubicin hydrochloride and paclitaxel should be performed with at least a 24 hour interval between the 2 agents.

Dexverapamil may alter the pharmacokinetics of epirubicin hydrochloride and possibly increase its bone marrow depressant effects.

One study found that docetaxel may increase the plasma concentrations of epirubicin hydrochloride metabolites, when administered immediately after epirubicin hydrochloride.

Quinine may accelerate the initial distribution of epirubicin hydrochloride from blood in to the tissues and may have an influence on the red blood cells partitioning of epirubicin hydrochloride.

The co-administration of interferon a2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin hydrochloride.

The possibility of a marked disturbance of haematopoiesis needs to be kept in mind with a (pre-) treatment with medications which influence the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, antiretroviral agents).

Increase of myelosuppression may occur in patients receiving combination therapy of anthracycline and dexrazoxane.

4.6 Fertility, pregnancy and lactation

(See section 5.3)

Epirubicin hydrochloride could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin hydrochloride should use effective contraceptive methods and if appropriate and available, seek advice on sperm preservation due to the possibility of irreversible infertility caused by therapy.

Epirubicin hydrochloride may cause amenorrhea or premature menopause in premenopausal wo­men.

Experimental data in animals suggest that epirubicin hydrochloride may cause fetal harm when administered to a pregnant woman. If epirubicin hydrochloride is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.

There are no studies in pregnant women. Epirubicin hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether epirubicin hydrochloride is excreted in human breast milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin hydrochloride, mothers should discontinue nursing prior to taking this drug.

4.7 Effects on ability to drive and use machines

There have been no reports of particular adverse events relating to effects on ability to drive and to use machines.

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with epirubicin with the following frequencies:

Intravesical administration:

As only a small amount of active ingredient is reabsorbed after intravesical instillation, severe systemic adverse drug reactions as well as allergic reactions are rare. Commonly reported are local reactions like burning sensation and frequent voiding (pollakisuria)­.Occasional bacterial or chemical cystitis have been reported (see section 4.4). These ADRs are mostly reversible.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Acute overdosage with epirubicin hydrochloride will result in severe myelosuppression (mainly leucopoenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucosal inflammation) and acute cardiac complications. Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment (see section 4.4). Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic. Epirubicin cannot be removed by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anthracyclines and related substances ATC code: L01D B03.

The mechanism of action of epirubicin hydrochloride is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin hydrochloride has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

5.2 Pharmacokinetic properties

In patients with normal hepatic and renal function, plasma levels after I.V. injection of 60–150 mg/m2 of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin hydrochloride and epirubicinol.

The 4'-O-glucuronidation distinguishes epirubicin hydrochloride from doxorubicin and may account for the faster elimination of epirubicin hydrochloride and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged drug.

Epirubicin hydrochloride is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution.

Urinary excretion accounts for approximately 9–10% of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The drug does not cross the blood brain barrier

5.3 Preclinical safety data

The main target organs in rat, rabbit and dog following repeated dosing were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs.

Epirubicin hydrochloride was also cardiotoxic in the species tested.

It was genotoxic, and, like other anthracyclines, carcinogenic in rats.

Epirubicin hydrochloride was embryotoxic in rats. No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, epirubicin hydrochloride must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin hydrochloride causes tissue necrosis.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride

Hydrochloric acid (For pH adjustment) Water for Injections

6.2 Incompatibilities

Epirubicin hydrochloride contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.

Epirubicin hydrochloride should not be mixed with heparin due to chemical incompatibility which may lead to precipitation when the drugs are in certain proportions.

Epirubicin hydrochloride can be used in combination with other antitumour agents, but it is not recommended that it be mixed with other drugs

6.3 Shelf life

Shelf life of the product as package for sale:

2 year.

Shelf life after first opening the container:

The vials are for single use only and any unused portion must be discarded after use. From a microbiological point of view, the product should be used immediately after the first penetration of the rubber stopper. If not used immediately, in use storage times and conditions are the responsibility of the user.

Shelf life after dilution of the solution for injection:

Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted, under aseptic conditions, in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2–8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage after dilution, see section 6.3.

6.5 Nature and contents of container

5 and 10 ml vials: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white seal.

25 ml vial: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white / royal blue seal.

50 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off royal blue seal.

100 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white / royal blue seal.

Pack size: 1 vial.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. For information on the stability of the infusion solutions, please refer to section 6.3.

The solution for injection or infusion contains no preservative and any unused portion of the vial should be discarded immediately in accordance with local requirements.